Enantioselective Enzymatic Desymmetrization of Highly

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                                                                               Enantioselective Enzymatic                                                                                                       2009
                                                                                                                                                                                                           Vol. 11, No. 21
                                                                               Desymmetrization of Highly Functionalized                                                                                    4950-4953
                                                                               Meso Tetrahydropyranyl Diols†
                                                                               Mathieu Candy, Gerard Audran, Hugues Bienayme,‡ Cyril Bressy,* and
                                                                                               ´                           ´
                                                                               Jean-Marc Pons*

                                                                                                      ´                           ´
                                                                               Aix-Marseille UniVersite, Institut des Sciences Moleculaires de Marseille, iSm2 CNRS
                                                                                           ´            ´                   ´ ˆ
                                                                               UMR6263 - equipe STeReO Campus Saint-Jerome, 13397 Marseille Cedex 20, France

                                                                               Received September 11, 2009
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       Publication Date (Web): October 7, 2009 | doi: 10.1021/ol902107g


                                                                               The enantioselective enzymatic desymmetrization of several highly substituted meso-tetrahydropyranyl diols is described. This transformation
                                                                               leads to valuable building blocks containing up to five stereogenic centers, which are revealed in a single step with both high yields and
                                                                               excellent enantiomeric excesses. Moreover, it was shown that this kind of building blocks could provide an easy access to both enantiomers
                                                                               of highly functionalized stereotetrads.

                                                                               Many natural products bear a tetrahydropyran (THP) moiety                       The enantioselective desymmetrization of meso com-
                                                                               and some, such as kendomycin,1 phorboxazoles,2 and rat-                      pounds has become a powerful strategy in synthesis9 as it
                                                                               jadone A,3 present interesting biological activities (Figure                 allows to reveal and/or generate multiple stereogenic centers
                                                                               1). This observation led chemists to develop strategies and                  in a single operation. Hence, in the context of total synthesis,
                                                                               new approaches to obtain this particular heterocycle in a                    the retrosynthetic analysis is based on the detection of hidden
                                                                               stereoselective fashion.4 Among these, the Prins reaction,5                  symmetry within the target molecule. The desymmetrization
                                                                               the Petasis-Ferrier rearrangement,6 the intramolecular oxa-                  of meso compounds containing functions such as epoxides,10
                                                                               Michael additions,7 and the hetero-Diels-Alder cycloaddi-
                                                                               tions8 have been widely adopted.                                                (2) Isolation: Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995,
                                                                                                                                                            117, 8126–8127. Total syntheses of Phorboxazole A: (a) Forsyth, C. J.;
                                                                                                                                                            Ahmed, F.; Cink, R. D.; Lee, C. S J. Am. Chem. Soc. 1998, 120, 5597–
                                                                                                                                                            5598. (b) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M.
                                                                                     Dedicated to Professor Mark Lautens on the occasion of his 50th        J. Am. Chem. Soc. 2001, 123, 10942–10953. (c) Gonzalez, M. A.; Pattenden,
                                                                               birthday.                                                                    G. Angew. Chem., Int. Ed. 2003, 42, 1255–1258. (d) Williams, D. R.;
                                                                                     TARGEON, 4 Avenue de l’Observatoire, 75006 Paris, France.              Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T.
                                                                                   (1) Isolation: Funahashi, Y.; Kawamura, N.; Ishimaru, T. Japan Patent    Angew. Chem., Int. Ed. 2003, 42, 1258–1262. (e) White, J. D.; Lee, T. H.;
                                                                               08231551 [A2960910], 1996; Chem. Abstr. 1997, 126, 6553; Japan Patent        Kuntiyong, P. Org. Lett. 2006, 8, 6039–6042. (f) White, J. D.; Lee, T. H.;
                                                                               08231552, 1996; Chem. Abstr. 1996, 125, 326518. Total syntheses: (a) Yuan,   Kuntiyong, P. Org. Lett. 2006, 8, 6043–6046. Total syntheses of Phorbox-
                                                                               Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720–14721. (b) Smith     azole B: (aa) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho,
                                                                               III, A. B.; Mesaros, E. F.; Meyer, E. A. J. Am. Chem. Soc. 2005, 127,        P. S. Angew. Chem., Int. Ed. 2000, 39, 2533–2536. (bb) Evans, D. A.; Cee,
                                                                               6948–6949. (c) Smith III, A. B.; Mesaros, E. F.; Meyer, E. A. J. Am. Chem.   V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew. Chem., Int. Ed. 2000,
                                                                               Soc. 2006, 128, 5292–5299. (d) Lowe, J. T.; Panek, J. S. Org. Lett. 2008,    39, 2536–2540. (cc) Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.;
                                                                               10, 3813–3816. (e) Magauer, T.; Martin, H. J.; Mulzer, J. Angew. Chem.,      Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem.sEur.
                                                                               Int. Ed. 2009, 48, 6032–6036. Formal syntheses: Bahnck, K. B.; Rych-         J. 2006, 12, 1185–1204. (dd) Lucas, B. S.; Gopalsamuthiram, V.; Burke,
                                                                               novsky, S. D. J. Am. Chem. Soc. 2008, 130, 13177–13180.                      S. D. Angew. Chem., Int. Ed. 2007, 46, 769–772.

                                                                               10.1021/ol902107g CCC: $40.75     2009 American Chemical Society
                                                                               Published on Web 10/07/2009
                                                                                                                                                                so far: (1) the enzyme-mediated hydrolysis of diesters19 or
                                                                                                                                                                mono-transesterification of diols which, when applied to
                                                                                                                                                                2,4,6-substitued meso-THP, lead to the generation of up to
                                                                                                                                                                three new stereogenic centers, and (2) the asymmetric ring-
                                                                                                                                                                opening cross-metathesis involving chiral catalysts.20
                                                                                                                                                                   In this paper, we report the synthesis of a new class of
                                                                                                                                                                meso compounds II bearing a 2,3,4,5,6-substituted tetrahy-
                                                                                                                                                                dropyranyl diol motif easily obtained from oxabicycles of
                                                                                                                                                                type I and their enantioselective enzymatic desymmetrization,
                                                                                                                                                                which reveals and creates up to five new stereogenic centers21
                                                                                                                                                                in a one-pot fashion (Scheme 1).

                                                                                                                                                                  Scheme 1. Synthetic Strategy toward THP Containing up to
                                                                                                                                                                                 Five Stereogenic Centers

                                                                               Figure 1. Natural products containing a highly substituted THP
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       Publication Date (Web): October 7, 2009 | doi: 10.1021/ol902107g

                                                                               anhydrides,11 diols12 and polyols,13 dienes,14 ketones,15 or
                                                                               oxabicycles16 has been successfully applied to the total
                                                                               synthesis of various challenging natural products.17 However,
                                                                               as highlighted by Hoffmann in a recent review,18 the use of                        The synthesis of the meso compounds relied on the
                                                                               meso compounds in asymmetric synthesis is greatly depend-                        oxabicycles of type I easily available through a highly
                                                                               ent on how easy these meso building blocks are built.                            diastereoselective [4 + 3] cycloaddition between furan
                                                                                 Syntheses of THP subunits through enantioselective de-                         derivatives and oxyallyl cation precursors following the
                                                                               symmetrization using a preformed THP ring are rare. Indeed,                      procedure developed by Lubineau and Bouchain22 (Scheme
                                                                               to our knowledge, only two methods have been described
                                                                                                                                                                    (12) For recent examples of enantioselective catalytic desymmetrization
                                                                                  (3) Isolation: Schummer, D.; Gerth, K.; Reichenbach, H.; Hofle, G.   ¨                                   ¨
                                                                                                                                                                of meso diols, see: (a) Kundig, E. P.; Enriquez Garcia, A.; Lomberget, T.;
                                                                               Liebigs Ann. 1995, 685–688. Total Syntheses: (a) Williams, D. R.; Ihle,          Perez Garcia, P.; Romanens, P. Chem. Commun. 2008, 3519–3521. (b)
                                                                               D. C.; Plummer, S. V. Org. Lett. 2001, 3, 1383–1386. (b) Bhatt, U.;              Birman, V. B.; Jiang, H.; Li, X. Org. Lett. 2007, 9, 3237–3240. (c) Zhao,
                                                                               Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse, M. J. Org. Chem.            Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006, 443, 67–70.
                                                                               2001, 66, 1885–1893.                                                             (d) Shimizu, H.; Onitsuka, S.; Egami, H.; Katsuki, T. J. Am. Chem. Soc.
                                                                                  (4) For a review on THP, see: (a) Clarke, P. A.; Santos, S. Eur. J. Org.      2005, 127, 5396–5413.
                                                                               Chem. 2006, 2045–2053. (b) Larrosa, I.; Romea, P.; Urpi, F. Tetrahedron              (13) For recent examples of enantioselective catalytic desymmetrization
                                                                               2008, 64, 2683–2723.                                                             of meso polyols, see: (a) Lucas, B. S.; Burke, S. D. Org. Lett. 2003, 5,
                                                                                  (5) For recent examples of Prins reaction in total synthesis, see: (a) Woo,   3915–3918. (b) Harada, T.; Egusa, T.; Igarashi, Y.; Kinugasa, M.; Oku, A.
                                                                               S. K.; Kwon, M. S.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 3242–3244.                                                       ˆ
                                                                                                                                                                J. Org. Chem. 2002, 67, 7080–7090. (c) Chenevert, R.; Rose, Y. S. J. Org.
                                                                               (b) Cheung, L. L.; Marumoto, S.; Anderson, C. D.; Rychnovsky, S. D. Org.         Chem. 2000, 65, 1707–1709.
                                                                               Lett. 2008, 10, 3101–3104. (c) Seden, P.; Charmant, J. P. H.; Willis, C. L.          (14) For examples, see: (a) Gerber-Lemaire, S.; Vogel, P. Eur. J. Org.
                                                                               Org. Lett. 2008, 10, 1637–1640. For a deeply mechanistic investigations,         Chem. 2003, 2959–2963. (b) Schreiber, S. L.; Goulet, M. T.; Schulte, G.
                                                                               see: Jasti, R.; Rychnovsky, S. D J. Am. Chem. Soc. 2006, 128, 13640–             J. Am. Chem. Soc. 1987, 109, 4718–4720.
                                                                               13648.                                                                               (15) For recent examples of catalytic desymmetrization of meso ketones,
                                                                                  (6) Smith III, A. B.; Fox, R. J.; Razler, T. M. Acc. Chem. Res. 2008,         see: (a) Chandler, C. L.; List, B. J. Am. Chem. Soc. 2008, 130, 6737–6739.
                                                                               41, 675–687.                                                                     (b) Ramachary, D. B.; Barbas, C. F. Org. Lett. 2005, 7, 1577–1580.
                                                                                  (7) For a general review on the Oxa-Michael including THP formation,              (16) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36,
                                                                               see: Nising, C. F.; Brase, S. Chem. Soc. ReV. 2008, 37, 1218–1228.
                                                                                                      ¨                                                         48–58.
                                                                                  (8) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,               (17) Some significant examples: Vannusal B: Nicolaou, K. C.; Zhang,
                                                                               Int. Ed. 1999, 38, 2398–2400.                                                    H.; Ortiz, A.; Dagneau, P. Angew. Chem., Int. Ed. 2008, 47, 8605–8610.
                                                                                  (9) Prochiral and meso compounds bearing with a mirror plan: Willis,          Tamiflu: Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J. Org. Chem. 2008, 73,
                                                                               M. C. J. Chem. Soc., Perkin Trans. 1999, 1, 1765–1784. Centro-symmetric          4895–4902. Ionomycin: Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith,
                                                                               molecules: Anstiss, M.; Holland, J. M.; Nelson, A.; Titchmarsh, J. R. Synlett    N. D.; Bouchain, G. Org. Lett. 2002, 4, 1879–1882. Quadrigemine C and
                                                                               2003, 1213–1220. Enzymatic desymmetrizations: Garcia-Urdiales, E.; Al-           Psycholeine: Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A.
                                                                               fonso, I.; Gotor, V. Chem. ReV. 2005, 105, 313–354.                              J. Am. Chem. Soc. 2002, 124, 9008–9009.
                                                                                  (10) For selected examples on catalytic enantioselective desymmetri-              (18) Hoffmann, R. W. Angew. Chem., Int. Ed. 2003, 42, 1096–1109.
                                                                               zation of meso epoxides by ring opening of a nucleophile, see: (a) Arai,             (19) (a) Lampe, T. F. J.; Hoffmann, H. M. R.; Bornsheuer, U. T.
                                                                               K.; Salter, M. M.; Yamashita, Y.; Kobayashi, S. Angew. Chem., Int. Ed.                                                                   ˆ
                                                                                                                                                                Tetrahedron: Asymmetry 1996, 7, 2889–2900. (b) Chenevert, R.; Goupil,
                                                                               2007, 46, 955–957. (b) Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.;           D.; Rose, Y. S.; Bedard, E. Tetrahedron: Asymmetry 1998, 9, 4285–4288.
                                                                               Yamamoto, N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc.               (20) (a) Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H.
                                                                               2000, 122, 2252–2260. (c) Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000,        J. Am. Chem. Soc. 2004, 126, 12288–12290. (b) Gillingham, D. G.;
                                                                               2, 1001–1004. By based-induced rearrangement, see: Sodergren, M. J.;             Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 3860–3864. (c) Ibrahem,
                                                                               Bertilsson, S. K.; Andersson, P. G. J. Am. Chem. Soc. 2000, 122, 6610–           I.; Yu, M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131,
                                                                               6618, and references therein.                                                    3844–3845.
                                                                                  (11) For a general review on enantioselective stereoselective ring opening        (21) We use the term “reveal” because the stereogenic centers pre-exist
                                                                               of meso anhydrides, see: Atodiresei, L.; Schiffers, I.; Bolm, C. Chem. ReV.      before the operation of desymmetrization and “create” because in our case
                                                                               2007, 107, 5683–5712.                                                            one carbon is prochiral (C4).

                                                                               Org. Lett., Vol. 11, No. 21, 2009                                                                                                                      4951
                                                                               2). Hence, multigram amounts of meso oxabicycle 1a could                    biguously by X-ray analysis of its corresponding iodide
                                                                               be obtained by simple crystallization of the crude material.                derivative 426 (Scheme 3).
                                                                               The synthetic sequence toward diol 2a from oxabicycle 1a
                                                                               required three steps: first, a highly stereoselective reduction
                                                                               of the ketone using sodium borohydride followed by an
                                                                               alkylation of the free hydroxyl group mediated by KH and                        Scheme 3. Synthesis of the Iodide Derivative 4 from the
                                                                               an ozonolysis [MeOH/CH2Cl2 (1.5/2), -60 °C] terminated                            Desymmetrized Compound 3a and Its ORTEP View
                                                                               by a reduction with an excess of sodium borohydride. Based
                                                                               on this strategy, a variety of meso-tetrahydropyranyl diols
                                                                               2a-i was synthesized.23

                                                                                 Scheme 2. Synthesis of the meso-Tetrahydropyranyl Diol 2a

                                                                                                                                                              We then examined the scope of the RML-promoted
                                                                                                                                                           desymmetrization using the variously substituted meso THP
                                                                                                                                                           diols 2a-i. The modification of the substituent at C4 on the
                                                                                                                                                           THP ring (R4) was first tested: the hydroxyl group in this
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                                                                                                                                                           position can be protected by several groups with different
                                                                                  Five commercially available lipases were screened.24 A                   hindrances without effect on the yields or the selectivities
       Publication Date (Web): October 7, 2009 | doi: 10.1021/ol902107g

                                                                               typical experiment was conducted at room temperature with                   (Table 2, entries 1-4). Even more interestingly, it appeared
                                                                               a mixture of meso diol 2a (0.245 mmol, 50 mg) and lipase                    that the inversion of configuration on C4 (Table 2, entry 5)
                                                                               (30 mg) in the presence of vinyl acetate25 (2 mL) and                       or the total reduction of this position (Table 2, entry 6) had
                                                                               diisopropyl ether (2 mL). The outcome of this initial                       no significant effect on ee. Increasing the steric hindrance
                                                                               screening indicated that Rhizomucor miehei lipase (RML)                     at C3 positions (R2) resulted only in a very slight decrease
                                                                               was the enzyme of choice for the transesterification of 2a                   of the enantioselectivity when a methyl was changed for an
                                                                               (Table 1, entry 3) leading to the corresponding monoacetate                 ethyl group (96% ee) (Table 2, entry 7), but a dramatic fall
                                                                               in high yield (90%) and excellent molecular recognition (ee                 of reactivity and enantioselectivity of the reaction was
                                                                               >98%) within 24 h. Pseudomonas fluorescens lipase (PFL)                      observed when a methyl group was changed for a phenyl
                                                                               also exhibited an interesting activity (Table 1, entry 2);                  group (Table 2, entry 8). Finally, desymmetrized THP 3i
                                                                               however, the yield and ee were slightly lower.                              bearing three quaternary centers could be obtained in 72%
                                                                                                                                                           yield and 94% ee from meso-triol 2i bearing a free tertiary
                                                                                                                                                           alcohol in C4 position.
                                                                                                                                                              We then explored the synthetic potential of the transfor-
                                                                               Table 1. Screening of Lipases for the Enantioselective                      mation and showed that the desymmetrized building block
                                                                               Enzymatic Desymmetrization of Tetrahydropyranyl Diols                       3a27 could easily be converted into both enantiomers 7 and
                                                                                                                                                           ent-7 of a syn-anti-anti stereotetrad just by changing the order
                                                                                                                                                           of the synthetic sequence (Scheme 4). Iodination of the free
                                                                                                                                                           primary alcohol of 3a followed by saponification, protection
                                                                                                                                                           of the alcohol as its p-methoxybenzyl ether using PMB-
                                                                                                                                                           trichloroacetimidate (PMBTCA) in the presence of a catalytic
                                                                                 entry        lipase        time (h)        yielda (%)       eeb (%)
                                                                                                                                                           amount of Yb(OTf)3,28 and a Zn-mediated ring-opening of
                                                                                                                                                           the THP ring furnished the valuable polyfunctionalized tetrad
                                                                                      1       PPL              48                0                         7 in 64% overall yield.
                                                                                      2       PFL              24               81             >94
                                                                                                                                                              Its enantiomer ent-7 could be obtained by starting with
                                                                                      3       RML              24               90             >98
                                                                                      4       CAL-B            20              100c                        the PMB protection, then saponification, followed by iodi-
                                                                                      5       CRL              20              100c                        nation and Zn-mediated ring-opening in a similar 69% overall
                                                                                     Isolated yields after column chromatography. b Determined by chiral   yield. In this non-aldol strategy to polypropionate fragments,
                                                                               HPLC (Sepapak-2-HR) after purification by column chromatography.
                                                                                 Formation of the meso-diacetate.                                             (24) PPL: Pig Pancreatic Lipase; PFL: Pseudomonas fluorescens; RML:
                                                                                                                                                           Rhizomucor miehei Lipase; CAL-B: Candida antarctica B Lipase; CRL:
                                                                                                                                                           Candida rugosa Lipase type VII.
                                                                                                                                                              (25) Vinyl acetate was used here as reagent and co-solvent to solubilize
                                                                                The absolute configuration of alcohol 3a, obtained through                  the meso diol during the desymmetrization reaction.
                                                                                                                                                              (26) CCDC 739869 contains the supplementary crystallographic data
                                                                               RML-promoted transesterification was determined unam-                        for this paper. These data can be obtained free of charge from the Cambridge
                                                                                                                                                           Crystallographic Data Centre via
                                                                                 (22) (a) Lubineau, A.; Bouchain, G. Tetrahedron Lett. 1997, 38, 8031–        (27) The desymmetrization of 2a was performed on 2 grams scale in
                                                                               8032. (b) Lautens, M.; Bouchain, G. Org. Synth. 2002, 79, 251–253.          87% and identical ee.
                                                                                 (23) See Supporting Information.                                             (28) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267–2269.

                                                                               4952                                                                                                                     Org. Lett., Vol. 11, No. 21, 2009
                                                                               Table 2. Enantioselective Enzymatic Desymmetrization of                       Scheme 4. Synthesis of Both Enantiomers 7 and ent-7 of the
                                                                               Tetrahydropyranyl Diols 2a-ia                                                syn-anti-anti-Tetrade from the Desymmetrized Monoacetate 3a
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       Publication Date (Web): October 7, 2009 | doi: 10.1021/ol902107g

                                                                                                                                                            lipase-catalyzed transesterification to afford tetrahydropyrans
                                                                                                                                                            with up to five stereogenic centers.
                                                                                                                                                               The reaction tolerated several variations on the structures
                                                                                                                                                            of these meso substrates with only slight effects on enantio-
                                                                                                                                                            selectivities and yields. We demonstrated the synthetic
                                                                                                                                                            potential of this kind of building block by obtaining both
                                                                                                                                                            enantiomers of a syn-anti-anti stereotetrad starting from the
                                                                                                                                                            same desymmetrized monoacetate 3a. Synthetic applications
                                                                                                                                                            of this novel methodology will be presented in due course.

                                                                                                                                                               Acknowledgment. We thank gratefully Professor P.
                                                                                                                                                            Kocienski (University of Leeds) for his interest in our work.
                                                                                                                                                            Dr N. Vanthuyne (chiral HPLC analysis) and Dr M. Giorgi
                                                                                                                                                            (X-ray analysis and determination of the absolute configu-
                                                                                                                                                            ration of compound 4) are deeply acknowledged. The
                                                                                     Typical experiment: diol 2a (0.245 mmol, 50 mg) and R. miehei lipase
                                                                               (30 mg) in i-Pr2O (2 mL) and vinyl acetate (2 mL), 24 h. b Isolated yields                       ´
                                                                                                                                                            University Paul Cezanne and the CNRS are gratefully
                                                                               after column chromatography. c Determined by chiral HPLC. d Reaction         acknowledged. M.C. thanks the CNRS and the Region       ´
                                                                               over 3 h, 27% of meso-diacetate was isolated. e Reaction over 72 h, 75%                        ˆ
                                                                                                                                                            Provence Alpes Cote d’Azur for funding.
                                                                               of diol was recovered.
                                                                                                                                                              Supporting Information Available: Full characterization
                                                                                                                                                            data and copies of 1H NMR and 13C NMR spectra of all
                                                                               it is important to note that the stereochemistry of the four
                                                                                                                                                            new compounds. This material is available free of charge
                                                                               stereogenic centers of the tetrad is controlled in a single step.
                                                                                                                                                            via the Internet at
                                                                                  In conclusion, a new class of meso-tetrahydropyranyl diols
                                                                               2a-i were synthesized that underwent efficient R. miehei                      OL902107G

                                                                               Org. Lett., Vol. 11, No. 21, 2009                                                                                                      4953

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